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HIV / AIDS & Opportunistic Infections www.hivma.org
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Learning Objectives HIV – the basics Epidemiology and screening New diagnosis and prognosis Antiretrovirals Opportunistic infections – clinical cases
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Human Retroviruses HTLV-1 Adult T-cell Leukemia, HAM/TSP HTLV-2 Possible association with HAM/TSP HIV-1 HIV-2 Extremely slow progression to AIDS SIV (Chimpanzee) HIV-1 Group M HIV-1 Group N HIV-1 Group O SIV (Sooty Mangabey) HIV-2
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HIV Infection White Blood Cells Lymphocytes T - Lymphocytes CD4+ T – Lymphocytes (Helper) CD4+ T – Lymphocytes CCR5+ (Memory)
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T-Cell Panel % CD3 63 % CD4 4 % CD8 55 CD3, Abs569 CD4, Abs38 CD8, Abs494 Normal CD4% >30% Normal CD4 >450 AIDS –CD4 < 200 –CD4% < 14% –OI –Malignancy Kaposi NHL Cervical cancer
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Who Should Be Tested? Routine HIV screening for all individuals ages 13-64 in all health-care settings. At least annual screening for high risk patients: –Injection drug use (sex partners) –Persons who exchange sex for money/drugs –MSM and sex partners of HIV infected persons –Heterosexuals (sex partner) with >1 sex partner since last HIV test Repeat test before new sexual relationship.
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HIV Test Routine HIV ELISA (HIV-1/O/2) - Positive Western Blot Rapid HIV ELISA - Negative Routine HIV ELISA - Positive Western Blot Window Period: - Routine HIV ELISA ~3 weeks - HIV Quantitative PCR ~7 days
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Initial Evaluation of New HIV HIV ELISA / WB CD4 count HIV Viral Load CBC w/ diff Comprehensive Chemistry Lipid profile Genotype resistance test Hepatitis A, B, C serologies RPR Toxoplasma serology Testing for GC/Chlamydia TST or IGRA HLA-B*5701 Urinalysis Thrush Genital & peri-anal lesions Pap smear Anal Pap smear (MSM) Lymphadenopathy Skin: KS lesions folliculitis psoriasis Neurologic: peripheral neuropathy neurosyphilis HAND / neuropsych testing Ophthalmologic ( CD4 < 50 )
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Prognosis http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf 3-yr probability of AIDS = AIDS defining illness or death, not CD4<200
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Natural Course of HIV Infection Plasma RNA Copies CD4 Cells 4-8 WeeksUp to 12 Years2-3 Years CD4 Cell Count 1,000 200 Intermediate StageAIDS Primary Infection Sero- conversion
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Opportunistic Infections – CD4 < 200 Pneumocystis pneumonia Oral candidiasis
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Opportunistic Infections – CD4 < 100 Toxoplasma encephalitis Candida esophagitis
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Opportunistic Infections – CD4 < 50 Disseminated cryptococcosis Kaposi sarcoma
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Opportunistic Infections – CD4 < 50 Molluscum contagiosum CMV Retinitis Many other… Disseminated Mycobacterium avium Progressive multifocal leukoencephalopathy Cryptosporidiosis & other protozoa
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AIDS Defining Illnesses Candidiasis Esophageal Tracheal, bronchial Cervical Cancer, invasive Coccidioides – disseminated Chronic diarrhea (>1 month) Cryptosporidia or Isospora Cryptococcus – extrapulmonary CMV Retinitis Other (not liver, spleen, LN) HSV Chronic ulcer (>1 month) Pulmonary, esophageal Histoplasma – disseminated HIV encephalopathy Kaposi’s sarcoma Lymphoma (NHL) Burkitt’s Immunoblastic Primary CNS Mycobacterium TB – any Other – disseminated/extrapulmonary Pneumonia Pneumocystis Recurrent bacterial (within 1 yr) PML NT Salmonella septicemia, recurrent Toxoplasmic encephalitis Wasting syndrome - HIV MMWR 1992; 41 (RR17)
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When to Start HAART? DHHS Guidelines 2011 (http://aidsinfo.nih.gov)
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Antiretrovirals Nucleoside RTI: Abacavir (Ziagen) Didanosine / ddI (Videx) Emtricitabine / FTC (Emtriva) Lamivudine / 3TC(Epivir) Stavudine / d4T (Zerit) Tenofovir (Viread) Zidovudine / AZT (Retrovir) Non-Nucleoside RTI: Efavirenz (Sustiva) Nevirapine (Viramune) Etravirine (Intelence) Rilpivirine (Edurant) Entry/Fusion Inhibitor: Enfuvirtide / T20(Fuzeon) Maraviroc (Selzentry) Protease Inhibitors: Atazanavir (Reyataz) Darunavir (Prezista) Fosamprenavir (Lexiva) Inidinavir (Crixivan) Lopinavir/Ritonavir (Kaletra) Nelfinavir (Viracept) Ritonavir (Norvir) Tipranavir (Aptivus) Integrase Inhibitor: Raltegravir (Isentress) Combinations: Atripla (Tenofovir + FTC + Sustiva) Combivir (AZT + 3TC) Epzicom (Abacavir + 3TC) Trizivir (AZT + Abacavir + 3TC) Truvada (Tenofovir + FTC)
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HIV Replicative Cycle
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ART Basics General concepts: –Need 3 active agents: ( 2 NRTI ) + ( NNRTI or PI or Integrase inhibitor ) –Treatment is life-long. Discontinuing ART results in viral rebound. Goal of therapy –HIV VL < 50 = “undetectable viral load” ART Resistance –Baseline resistance –Suboptimal medication adherence (90-95% compliance) –Suboptimal pharmacokinetics –Suboptimal potency of the regimen –Resistant strains are “archived” = permanent Common initial regimens: Atripla (Tenofovir + FTC + Sustiva) - QD Truvada + Reyataz + Norvir - QD Truvada + Isentress - BID Combivir + Kaletra - BID
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Can We Eradicate Infection? Nature Medicine 2003; 9:853-860
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Common adverse reactions Rash –Any antiretroviral –Mild to severe (SJS) –First 2 months Nausea/Vomiting –Any antiretroviral –R/O hepatitis –Symptomatic management Diarrhea –Any, but usually PIs –Symptomatic management Renal failure –Tenofovir (Truvada/Atripla) –First several months CNS/Psychiatric –Efavirenz (Sustiva/Atripla) –First several weeks Drug-Drug Interaction –New prescriptions Fluticasone, Statins PPIs –OTC St. John’s Wort
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When Should You Stop HAART? Patient clearly non-compliant (active drug abuse) – not “stopping” and actually “starting” Severe drug reaction: Abacavir hypersensitivity reaction – fever, rash, GI, and/or pulmonary symptoms within 6 weeks of initiation, association with HLA-B*5701. Lactic acidosis (ddI/d4T>AZT) – malaise, myalgias, non-specific symptoms or critically ill, pancreatitis/hepatitis, elevated serum lactate and acidemia. NNRTI hypersensitivity – occurs within 6 weeks of initiation, hepatitis (fulminant hepatic failure) and/or rash (Stevens-Johnson). Nevirapine hepatotoxicity risk factors: pregnancy, HBV/HCV, CD4 > 250 [ F ] or CD4 > 400 [ M ].
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HIV-Associated Dyslipidemia Fat Accumulation HIV Lipohypertrophy Increase abdominal fat Dorsocervical fat pad Metabolic Changes Increased Triglycerides Increased LDL Decreased HDL Insulin resistance
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Case #1 31 M with history of HIV presents with fevers and progressive DOE x 3 weeks. He reports he was diagnosed with HIV about 10 years ago when he developed shingles. He never followed-up and has never been on HAART. He does not know his last CD4 count or viral load.
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Case #1 ROS: 20 lbs weight loss x1 year Night sweats for past month Diarrhea SH: Acquired by MSM Born & raised in Ohio Moved to AZ 2 yrs ago Visits homeless shelters Physical Exam: 101.8 0 F 94 110/60 16 Pulse Ox 92% GEN – appears comfortable OP – thrush LUNGS – diffuse crackles ABD – soft, non-tender SKIN – no lesions MS – alert & oriented
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CXR
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Laboratory Results CD3 87 CD4 9 CD8 75 CD3, Abs610 CD4, Abs64 CD8, Abs530 HIV VL 500K
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Differential Diagnosis?
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Differential Diagnosis Pneumonia in HIV CAP – Pneumococcus, Influenza Pneumocystis TB Coccidioides Histoplasma Cryptococcus
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Diagnostic Tests Nasal Influenza swab - negative Blood cultures - negative Urine S.pneumonia antigen - negative Sputum culture - normal flora Sputum AFB smear - negative x3 Sputum fungal smear - negative Induced sputum PCP DFA - negative Serum Cryptococcal antigen - negative Coccidioides ELISA - negative
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Pneumocystis jiroveci Subtle – symptoms for weeks to months 90% with CD4 < 200 or CD4% < 15% CXR findings variable – possibly negative Negative CXR – role of HRCT Diagnosis: –Induced Sputum DFA 50-90% –BAL DFA 90-99% –Transbronchial Bx 95+%
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Therapy P a O 2 < 70 mmHg A-a > 35 mmHg Corticosteroids IV TMP/SMX IV Pentamidine PO TMP/SMX Clinda + Primaquine TMP/Dapsone Atovaquone - Clinical deterioration common within 3-5d of initiation of therapy, particularly in those not receiving corticosteroids. - Treatment failure if no improvement or worsening after at least 4-8d of therapy.
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Prophylaxis TMP/SMX, Dapsone, Atovaquone, Aero Pentamidine Stop prophylaxis when CD4 > 200 x 3 months 2 0 Prophylaxis: -Requires QD TMP/SMX, not QMWF 1 0 Prophylaxis: - CD4 < 200, or CD4% < 14% - History of thrush - AIDS defining illness
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Pneumonia in HIV S.pneumoniae remains most common cause. Other organisms = H.influenza, S.aureus, P.aeruginosa. Give Pneumovax and revaccinate when CD4 > 200. Pulmonary TB in HIV patients with CD4 > 350 similar to that in non-HIV infected individuals. Pulmonary TB in AIDS patients – typically no cavitation, appears more like consolidation or diffuse infiltrates. TB in HIV patients – at higher risk of extrapulmonary disease at all CD4 counts. AIDS patients and HIV patients with unknown CD4 count presenting with pneumonia Respiratory Isolation.
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Coccidioides Common cause of pneumonia in Arizona CD4 < 250, past history NOT a risk factor Radiographs – diffuse or focal infiltrates Serologic tests ~60% sensitivity Diagnosis – fungal culture, smear ~40% Disseminated disease frequent: lymph nodes, meningitis, skin
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Case #2 42 M with history of IVDA presents with complaints of intermittent fever, HA, and increasing lethargy over the past 4 weeks. He is subsequently found to be HIV + with a CD4 count of 23. He reports having been in and out of jail on several occasions. Poor historian, appears confused.
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MRI Brain
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Differential Diagnosis?
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Differential Diagnosis CNS Lesions in HIV Toxoplasma Encephalitis Primary CNS Lymphoma Bacterial brain abscess Progressive Multifocal Leukoencephalopathy TB Cryptococcus CMV Encephalitis Chagas disease
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Diagnostic Tests Blood cultures - negative Serum Cryptococcal antigen - negative Toxoplasma IgG positive, IgM negative LP: 8 WBC (90%L), 64 G, 60 P –Toxoplasma DNA PCR negative –CMV and JC virus PCRs negative –TB PCR negative –Cryptococcal antigen negative
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Toxoplasma Encephalitis 80% have CD4 < 100 95+% Toxoplasma IgG+ ~30% single lesion CSF PCR sensitivity 50% Definitive dx = brain bx Therapy – 6 wks Pyrimethamine/Sulfadiazine Pyrimethamine/Clindamycin 1 0 Prophylaxis ( CD4 < 100 ) DS TMP/SMX QD Pyrimethamine/Dapsone Adapted from http://www.cdc.gov
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Cryptococcal Meningitis Majority of cases occur in patients with CD4 < 50. Classic meningeal symptoms/signs (neck stiffness & photophobia) infrequent. Disseminated disease common: pulmonary, blood, skin. Elevated opening pressure > 75% (> 20cm H 2 O). Cryptococcal antigen 90+% sensitive (serum & CSF). Treatment: Ampho B +/- Flucytosine x 2wks Fluconazole Repeated LP for symptomatic elevated ICP
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Case #3 29M diagnosed with AIDS ~2 months ago (Thrush), started on HAART 6 weeks ago. Presents with acute onset of fever, cough, pleuritic chest pain, and dyspnea. He looks well despite Temp 102.6 0 F. Exam only notable for L sided bronchial breath sounds. CD4 count 29 146.
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CXR
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CT Chest
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Laboratory Studies Blood cultures Fungal BC Mycobacterial BC Serum Cryptococcal Ag Urine Histoplasma Ag RPR LDH 188 WBC 12.9 (88%N) BAL Bacterial Cx - BAL Fungal Cx - BAL Mycobacterial Cx - BAL PCP DFA - BAL Viral Cx - BAL Cytology: WBC/RBC, benign bronchial cells Transbronchial Bx: Bronchial mucosa - crush artifact
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Diagnosis?
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Lymph node biopsy reveals caseating granulomata with rare acid fast organisms LN Mycobacterial culture - MAC
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Disseminated MAC Occurs in advanced AIDS, CD4 < 50. Vast majority – fevers, weight loss, night sweats, severe anemia (Hct < 25%). Organ involvement: spleen, LN, liver, intestines, and bone marrow. Lung involvement rare (< 10%). Diagnosis: –Blood culture – single 90-95%, two 99%. –May take 2-6 weeks to grow. Treatment: Clarithromycin + Ethambutol +/- Rifabutin 1 0 Prophylaxis ( CD4 < 50 ): Azithromycin 1200mg Qwk
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Immune Reconstitution Inflammatory Syndrome Paradoxical worsening of clinical or laboratory parameters despite rising CD4 counts and declining viral loads. Inflammatory reaction to a subclinical infection. Estimated to occur in 10- 25% of those initiating ART (weeks to months). CID 2004; 38:1159-66
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Summary HIV –HIV-1/0/2 strains. CD4 T-cell, CCR5 > CXCR4. LN damage. Epidemiology and screening –About 50,000 new cases / yr. MSM > heterosexual > IVDA. –HIV EIA HIV WB. Check VL for acute retroviral syndrome. New diagnosis and prognosis –Screen for other STIs. Baseline genotype resistance testing. Antiretrovirals –Indications: CD4 < 350, AIDS, HIVAN, HBV trmt, pregnancy –Need 3 active agents, strict compliance, lifelong treatment Opportunistic infections –Primary Prophylaxis: PJP, Toxoplasma, MAC –Cryptococcus, CMV, Cryptosporidia –IRIS – unmasking versus paradoxical
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